PT  - JOURNAL ARTICLE
AU  - Ersoy, Baran A.
AU  - Tarun, Akansha
AU  - D’Aquino, Katharine
AU  - Hancer, Nancy J.
AU  - Ukomadu, Chinweike
AU  - White, Morris F.
AU  - Michel, Thomas
AU  - Manning, Brendan D.
AU  - Cohen, David E.
TI  - Phosphatidylcholine Transfer Protein Interacts with Thioesterase Superfamily Member 2 to Attenuate Insulin Signaling
AID  - 10.1126/scisignal.2004111
DP  - 2013 Jul 30
TA  - Science Signaling
PG  - ra64--ra64
VI  - 6
IP  - 286
4099  - http://stke.sciencemag.org/content/6/286/ra64.short
4100  - http://stke.sciencemag.org/content/6/286/ra64.full
SO  - Sci. Signal.2013 Jul 30; 6
AB  - Phosphatidylcholine transfer protein (PC-TP) is a phospholipid-binding protein that is enriched in liver and that interacts with thioesterase superfamily member 2 (THEM2). Mice lacking either protein exhibit improved hepatic glucose homeostasis and are resistant to diet-induced diabetes. Insulin receptor substrate 2 (IRS2) and mammalian target of rapamycin complex 1 (mTORC1) are key effectors of insulin signaling, which is attenuated in diabetes. We found that PC-TP inhibited IRS2, as evidenced by insulin-independent IRS2 activation after knockdown, genetic ablation, or chemical inhibition of PC-TP. In addition, IRS2 was activated after knockdown of THEM2, providing support for a role for the interaction of PC-TP with THEM2 in suppressing insulin signaling. Additionally, we showed that PC-TP bound to tuberous sclerosis complex 2 (TSC2) and stabilized the components of the TSC1-TSC2 complex, which functions to inhibit mTORC1. Preventing phosphatidylcholine from binding to PC-TP disrupted interactions of PC-TP with THEM2 and TSC2, and disruption of the PC-TP–THEM2 complex was associated with increased activation of both IRS2 and mTORC1. In livers of mice with genetic ablation of PC-TP or that had been treated with a PC-TP inhibitor, steady-state amounts of IRS2 were increased, whereas those of TSC2 were decreased. These findings reveal a phospholipid-dependent mechanism that suppresses insulin signaling downstream of its receptor.